Cycloid psychoses are not part of a bipolar affective spectrum: results of a controlled family study.

BACKGROUND: Whereas a growing body of evidence suggests that cycloid psychoses have to be separated from schizophrenic psychoses, their relations to bipolar affective disorder are less clear. To further clarify this issue a controlled family study was undertaken. METHODS: All living and traceable adult first-degree relatives of 45 cycloid psychotic, 32 manic-depressive and 27 control probands were personally examined by an experienced psychiatrist blind to the diagnosis of the index proband. Data about not traceable relatives were collected by the "Family-History"-Method. A catamnestic diagnosis was established for each of the 431 relatives blind to family data. Age-corrected morbidity risks were calculated using the life-table method. RESULTS: Relatives of cycloid psychotic patients showed a significantly lower morbidity risk for endogenous psychoses in general and manic-depressive illness compared to relatives of patients with manic-depressive illness. The familial morbidity risk for cycloid psychoses was low and did not differ significantly in both proband groups. Relatives of cycloid psychotic patients however did not differ significantly from relatives of controls regarding familial morbidity. LIMITATIONS: Our time-consuming methodical procedure implicated a relatively small number of participants due to restricted personnel resources. The restriction to hospitalised probands could possibly cause a limited representativity of the study sample. CONCLUSIONS: Our results suggest that cycloid psychoses are aetiologically different from manic-depressive illness and could not be integrated into a spectrum of bipolar affective disorders. The findings provide further evidence for a nosological independence of cycloid psychoses.

Exposure to prenatal infections, genetics and the risk of systematic and periodic catatonia.

The meaning of heterogeneity in schizophrenia and the impact of genetic and environmental factors on etiology are a matter of continuous debate in psychiatric research. Different clinical and birth history variables were investigated in a sample of 68 patients with chronic catatonic schizophrenia according to DSM III-R, classified into Leonhard's systematic schizophrenia (n = 32) and periodic catatonia (n = 36). Parental transmission of the disease was evident in 44% of the periodic catatonia cases compared to one case in systematic catatonia (3%; p = 0.0003). In systematic catatonia, 34% of the index cases were exposed to prenatal infections compared to 8% in periodic catatonia (p = 0.008). Using logistic regression analysis exposure to gestational maternal infections predicted diagnosis of systematic catatonia at p = 0.008, and parental psychosis predicted diagnosis of periodic catatonia in the index cases at p = 0.0001. The latter finding is substantiated by the recent mapping of a periodic catatonia-susceptibility locus on chromosome 15q15 with evidence for autosomal dominant transmission. These findings support the hypothesis that distinct schizophrenia phenotypes are based on different etiological mechanisms.

A genome screen for genes predisposing to bipolar affective disorder detects a new susceptibility locus on 8q.

Bipolar affective disorder (BPAD), also known as manic depressive illness, is a severe psychiatric disorder characterized by episodes of mania and depression. It has a lifetime prevalence of approximately 1% in all human populations. In order to identify chromosomal regions containing genes that play a role in determining susceptibility to this psychiatric condition, we have conducted a complete genome screen with 382 markers (average marker spacing of 9.3 cM) in a sample of 75 BPAD families which were recruited through an explicit ascertainment scheme. Pedigrees were of German, Israeli and Italian origin, respectively. Parametric and non-parametric linkage analysis was performed. The highest two-point LOD score was obtained on 8q24 (D8S514; LOD score = 3.62), in a region that has not attracted much attention in previous linkage studies of BPAD. The second best finding was seen on 10q25-q26 (D10S217; LOD score = 2.86) and has been reported in independent studies of BPAD. Other regions showing 'suggestive' evidence for linkage localized to 1p33-p36, 2q21-q33, 3p14, 3q26-q27, 6q21-q22, 8p21, 13q11 and 14q12-q13. In addition, we aimed at detecting possible susceptibility loci underlying genomic imprinting by analyzing the autosomal genotype data with the recently developed extension of the GENEHUNTER program, GENEHUNTER-IMPRINTING. Putative paternally imprinted loci were identified in chromosomal regions 2p24-p21 and 2q31-q32. Maternally imprinted susceptibility genes may be located on 14q32 and 16q21-q23.

[Autistic hebephrenia: concepts and findings]. / Die autistische Hebephrenie - Konzept und Befunde

The concept of hebephrenia according to Kleist and Leonhard describes distinct clinical entities with a chronically progressive course leading to residual syndroms with a clear cut symptom constellation which is stable over time. The main symptom is a specific kind of pathological affectivity resulting in a lack of profound future- orientated tension. In six case-reports we illustrate the characteristical clinical picture of the autistic hebephrenia, one of the four subforms of hebephrenic psychoses according to Leonhard. The characteristical clinical syndrom consists of an affective blunting, autistic withdrawal, unfathomable facial expression, unhappy mood and periods of moodiness with aggressive excitement. The concept of hebephrenia according to Kleist and Leonhard presents a promising heuristic attempt for biological-etiological research. In ICD-10 and DSM-IV the usual concept of hebephrenia is a rather vaguely defined nosological category with a polymorphous non-specific symptomatology.

Association between the 5' UTR variant C178T of the serotonin receptor gene HTR3A and bipolar affective disorder.

Serotonin receptor type 3 is a ligand-gated ion channel implicated in behavioural disorders. Our objective was to identify nucleotide variants in a specific portion of the 5' region of the serotonin receptor gene (HTR3A) containing upstream open reading frames (uORFs) and to investigate their effect on bipolar disease. Mutations in uORFs have been recently shown to cause disease by changing expression on the translational level. We identified one polymorphism, C195T, and one missense mutation, C178T (Pro16Ser) within an upstream open reading frame. No significant association was found between the C195T polymorphism and bipolar affective disorder. A significant association was, however, found between the variant C178T in 156 patients with bipolar disorder compared to 156 healthy controls (P = 0.00016). To investigate the relevance of this variant on gene expression, luciferase reporter constructs containing the C178T (Pro16Ser) allele were established and compared to the C178T plus C195T and wild-type alleles. Reporter constructs containing the C178T (Pro16Ser) allele drove 245% and 138% expression compared to the wild-type allele. These findings show that the C178T(Pro16Ser) variant in HTR3A may represent a functional variant and affect the susceptibility to bipolar disorder.

A possible susceptibility locus for bipolar affective disorder in chromosomal region 10q25--q26.

In an attempt to identify susceptibility loci for bipolar affective disorder, we are currently conducting a systematic genome screen with highly polymorphic microsatellite markers at an average marker spacing of 10 cM in a series of 75 families, comprising 66 families from Germany, eight families from Israel, and one family from Italy. The families were ascertained through index cases with bipolar affective disorder. The distribution of diagnoses is as follows: 126 individuals with bipolar I disorder, 40 with bipolar II disorder, 14 with schizoaffective disorder of the bipolar type, 40 individuals with recurrent unipolar depression, 51 with a minor psychiatric diagnosis, and two individuals with a diagnosis of schizophrenia. One hundred and seventy-one individuals are unaffected. Here, we present results from chromosome 10. Linkage analyses using a total of 33 microsatellite markers with parametric and non-parametric methods provided evidence for linkage at chromosomal region 10q25--q26. The highest two-point LOD score (2.86, theta = 0.05) was obtained for D10S217 using a dominant genetic model and a broad definition of affection status. The GENEHUNTER program localized the putative susceptibility locus within a ca 15-cM interval between markers D10S1483 and D10S217 with a maximum NPL(all) score of 3.12 (P = 0.0013). Positive linkage findings that have been reported by two independent studies further support the hypothesis of a susceptibility gene for bipolar affective disorder on 10q25-q26.

[Hypochondriacal euphoria as a special form of monopolar affective psychosis]. / Die hypochondrische Euphorie als Sonderform einer monopolaren affektiven Psychose.

BACKGROUND: In contemporary concepts of affective psychoses the existence of monopolar manias is widely questioned. Nevertheless, cases of manias with monomorphous symptomatology are reported repeatedly from all over the world. Based upon subtle observation of signs and course over many years, Karl Leonhard developed a concept of affective psychoses that permits a distinction of monopolar from bipolar forms, e.g. monopolar manias and euphoric euphorias. METHODS: As an example for the pure forms of euphorias we present two cases of hypochondriacal euphoria. CONCLUSION: We discuss some of the literature relevant to the issue and propose the application of a differentiated psychopathological analysis for the discrimination of monopolar from bipolar manias.

Serotonin receptor gene HTR3A variants in schizophrenic and bipolar affective patients.

Serotonin receptor genes have always been considered excellent candidate genes in the aetiology of neurogenetic diseases. In this study, we assessed sequence variations of the HTR3A gene. For this purpose, we established exon-specific primers and analysed DNA samples from 165 unrelated individuals including 70 schizophrenic patients, 48 patients with bipolar affective disorder and 47 healthy control persons using polymerase chain reaction/single-strand conformational polymorphism analysis. We discovered six sequence variants, five of which represent polymorphisms. These polymorphisms could not be associated with schizophrenia and bipolar affective disorder (P = 0.055-1). We also detected a missense mutation in exon 9 in a schizophrenic patient at a conserved position (Pro391Arg). To determine the incidence of this substitution an extended set of 358 schizophrenic patients and 155 control individuals was investigated. The Pro391Arg mutation was not detected in these schizophrenic patients and controls screened. However, a second missense mutation (Arg344His) was detected in one schizophrenic patient, but not in any of the controls. These results suggest that the observed mutations in HTR3A are rare and therefore do not play a major role in the aetiology of the disorder. Further studies are needed to support the hypothesis that HTR3A may contribute to the schizophrenia in these patients.

Towards the genetic basis of periodic catatonia: pedigree sample for genome scan I and II.

In a genome-wide linkage study, we mapped two major susceptibility loci for periodic catatonia, a phenotype with qualitative disturbances of the psychomotor sphere and a morbidity risk of 26.9% in first-degree relatives of index cases, to chromosome 15q15, and to chromosome 22q13 using nonparametric as well as parametric (autosomal dominant model) analyses. The study included 12 multiplex pedigrees with 135 individuals, among them 57 affected persons. A second genome scan is in progress investigating four families with 21 affected individuals, aiming to confirm linkage results. Age at onset patterns as well as the clinical outcome were similar among affected individuals in both sets of families. Within the pedigrees we observed no physical diseases segregating with periodic catatonia. Under the assumption of genetic homogeneity, the statistical power to detect LOD scores > or = 2.0 was 98.5% in the first set of families, and 57.9% in the second set. Thus, the panel of multiplex pedigrees segregating periodic catatonia seems to represent a homogenous clinical sample, and possesses sufficient statistical power to delineate and confirm linkage to major genetic loci for periodic catatonia.

Splitting schizophrenia: periodic catatonia-susceptibility locus on chromosome 15q15.

The nature of subtypes in schizophrenia and the meaning of heterogeneity in schizophrenia have been considered a principal controversy in psychiatric research. We addressed these issues in periodic catatonia, a clinical entity derived from Leonhard's classification of schizophrenias, in a genomewide linkage scan. Periodic catatonia is characterized by qualitative psychomotor disturbances during acute psychotic outbursts and by long-term outcome. On the basis of our previous findings of a lifetime morbidity risk of 26.9% of periodic catatonia in first-degree relatives, we conducted a genome scan in 12 multiplex pedigrees with 135 individuals, using 356 markers with an average spacing of 11 cM. In nonparametric multipoint linkage analyses (by GENEHUNTER-PLUS), significant evidence for linkage was obtained on chromosome 15q15 (P = 2.6 x 10(-5); nonparametric LOD score [LOD*] 3.57). A further locus on chromosome 22q13 with suggestive evidence for linkage (P = 1.8 x 10(-3); LOD* 1.85) was detected, which indicated genetic heterogeneity. Parametric linkage analysis under an autosomal dominant model (affecteds-only analysis) provided independent confirmation of nonparametric linkage results, with maximum LOD scores 2.75 (recombination fraction [theta].04; two-point analysis) and 2.89 (theta =.029; four-point analysis), at the chromosome 15q candidate region. Splitting the complex group of schizophrenias on the basis of clinical observation and genetic analysis, we identified periodic catatonia as a valid nosological entity. Our findings provide evidence that periodic catatonia is associated with a major disease locus, which maps to chromosome 15q15.

[The effect of the menstruation cycle on manifestations of pychiatric diseases]. / Der Einfluss des Menstruationszyklus auf die Manifestation psychiatrischer Erkrankungen.

In the present study we investigated whether a correlation exists between menstrual cycle phase on the day of an acute psychiatric admission and diagnostic entities. Therefore we assessed the menstrual cycle phase in 155 women at the time of acute admission for any non-organic psychiatric disorder. A specific diagnosis according to ICD-10-criteria and to Leonhard's nosology was established without knowledge of the menstrual cycle phase. Independent of diagnosis and classification, the majority of patients (57%) was admitted during the pre-menstrual/menstrual period. Comparing the frequencies of admission before (increasing blood-estrogen-level) and after ovulation (decreasing blood-estrogen-level) we found using ICD-10 criteria there were no significant differences between affective psychoses (F3), acute polymorphous psychotic disorder (F23), schizophrenia/schizoaffective psychoses (F20 and F25) and patients suffering from neuroses or personality disorders (F4-F6). Applying Leonhard's criteria we found no significant differences between endogeneous psychoses and personality disorders and no significant differences between cycloid psychoses and affective psychoses or affective psychoses and schizophrenias as well. However, patients with cycloid psychoses were significantly more frequently admitted to hospital during the luteal-/menstrual phase than patients with schizophrenia (chi 2-Test, p = 0.02). These findings do not confirm a specificity of a pre-menstrual exacerbation of psychotic symptoms for schizophrenia. Rather we found cycloid psychoses to be significantly more frequently associated with premenstrual exacerbation of symptoms.

Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1).

The dopamine transporter (DAT) plays a central role in dopaminergic neurotransmission in the human brain. Genetic association studies have used a variable number of tandem repeat (VNTR) polymorphism in the 3'-flanking region of the dopamine transporter gene (DAT1) to implicate the DAT in the development of various neuropsychiatric disorders. In this study, we have examined the possibility that a mutation exists in the coding region of the DAT1 gene which through linkage disequilibrium accounts for the observed associations. The complete coding region, as well as exon-intron boundaries, was screened in 91 unrelated individuals including 45 patients with bipolar affective disorder and 46 healthy control individuals by the means of single strand conformation analysis. Our findings suggest that the DAT1 gene is highly conserved since we detected only two rare missense substitutions (Ala559Val, Glu602Gly) and three silent mutations (242C/T, 1342A/G, and 1859C/T) in the whole coding region. Five sequence variants were observed in intronic sequences but none affects known splice sites. The lack of frequent variants of possible functional relevance indicates that genetic variation in the coding region of the DAT1 gene is not responsible for the previously observed associations with neuropsychiatric disorders. The two rare missense substitutions were found in single bipolar patients but not in controls. Investigation of the patients' families revealed independent segregation between the Ala559Val variant and affective disorder. The Glu602Gly variant was inherited by the proband from an affected father. It therefore remains possible that Glu602Gly may be a rare cause of bipolar affective disorder.

Association study of the tryptophan hydroxylase gene and bipolar affective disorder using family-based internal controls.

The tryptophan hydroxylase (TPH) gene encodes for the rate-limiting enzyme of the serotonin metabolism and, therefore, has to be considered a major candidate for association studies in affective disorders. Recently, an association between this gene and bipolar affective disorder has been reported in a French population. We sought to replicate this finding in a German sample. Allele frequencies of a biallelic polymorphism (A218C) of the TPH gene were determined in 95 bipolar I patients and their parents. Preferential transmission of alleles from heterozygous parents to bipolar offspring was tested with the "transmission disequilibrium test" (TDT), which eliminates the contribution of population stratification to an association finding. Our sample yielded a power >90% to detect the originally reported effect. Neither allele 218A nor allele 218C were preferentially transmitted from heterozygous parents to bipolar offspring. Our results, therefore, do not support the hypothesis that the TPH gene is involved in the etiology of bipolar disorder.

Cavum veli interpositi and psychotic disorder in a monocygotic twin.

The case of monocygotic twins discordant for a psychotic disorder is presented. An anomaly of the septum pellucidum, a so-called cavum veli interpositi was found in the psychotic twin while his brother showed no such anomaly. Previous studies have shown a higher prevalence of septum pellucidum anomalies in schizophrenic patients. Abnormalities of the septum pellucidum may be associated with disturbed neuronal development in distinct limbic brain areas which cannot yet be visualized yet by brain imaging techniques. The finding of the cavum veli interpositi in the psychotic twin could be incidental; however, it may indicate a dysgenic process in early brain development and, thus, play a significant role in the etiology of psychosis.

[Differential diagnosis, course and outcome of postpartum psychoses. A catamnestic investigation]. / Differenzierte Diagnostik, Verlauf und Ausgang postpartaler Psychosen. Eine katamnestische Untersuchung.

In a polydiagnostic study, a systematically recruited collective of 34 women with a first-episode postpartum psychosis was reexamined after a period of 6-26 years (averaging 12.6 years) in order to establish lifetime-diagnoses according to ICD-10 and Leonhard's classification, and to determine course and outcome. According to ICD-10, unipolar depressive disorders (32%) and acute polymorphous psychotic disorders (28%) represented the most frequent diagnoses. Applying Leonhard's classification revealed a marked predominance of cycloid psychoses (62%) with the subform of motility psychosis being the most frequent diagnosis (38%). Schizophrenias occurred rarely according to both classifications. Investigating the long-term course, we found in 59% multiphasic disorders. The mean number of episodes per patient was 2.5 (range 2-6) with a mean duration of 9.8 weeks (SD = 5.2). 6 patients (18%) had undergone a monophasic course, in 4 cases (12%) the course was not determinable. 17 women (50%) had 19 further deliveries during the follow-up period. The frequency of relapses in connection with a further delivery was 47%. Administering the Strauss-Carpenter-Outcome-Scale revealed a favourable outcome with a mean value of 14.1 (SD = 2.83) for our total sample. Only 4 patients (12%) had never recovered fully since the onset of the illness. Our findings suggest that cycloid psychoses, in particular motility psychoses, account for the majority of postpartum psychoses, and do not support the hypothesis of a nosological independence of postpartum psychoses. They provide further evidence of a favourable prognosis of severe postpartum psychiatric disorder despite a relatively high rate of non-puerperal and especially puerperal relapses.

The genetic heterogeneity of "schizophrenia".

The main reason for the inconsistent findings in schizophrenia research is the lack of diagnostic conformity. This has not changed markedly following the introduction of modern operational diagnostic systems. Taking schizophrenia as a disease entity or assuming schizophrenia spectrum psychoses to represent a continuum of diseases without any clear dividing lines, the results of family and twin studies point to a multifactorial etiology based on a polygenic mode of transmission. Further, then it has to be assumed a familial continuum from schizophrenia to affective psychosis and other spectrum disorders. However, in family and twin studies based on Leonhard's classification, there is clearcut evidence that schizophrenic spectrum psychoses have to be divided into clinical and etiological subgroups with a completely different genetic background. For example, systematic catatonia is, for the most part, a sporadic disease, whereas periodic catatonia aggregates in families in a manner consistent with a major gene effect. Further, the results indicate that schizophrenic spectrum psychoses consist of three main valid categories: cycloid psychoses, unsystematic schizophrenias and systematic schizophrenias. In the case of cycloid psychosis and systematic schizophrenias, genetic loading seem to be very low, while "environmental" factors, for example, birth complications, may play an important etiological role. Unsystematic schizophrenias, however, are predominantly inherited and "environmental" factors are not very prominent.

Long-term course and outcome of severe postpartum psychiatric disorders.

Thirty-nine women who had suffered from a severe first-episode postpartum psychiatric illness were re-examined after a period of 6-26 years (averaging 12.5 years). Diagnoses were established according to ICD-10 and Leonhard's classification, revealing a marked predominance of cycloid psychoses (54%) according to Leonhard. There was no evidence of the nosological independence of postpartum psychosis. Only 4 patients (10%) had never recovered fully since the onset of the illness. In contrast, 6 patients had undergone a monophasic course without any further psychopathology. In 20 cases (51%) the illness had run a multiphasic course. The average number of episodes per patient was 2.5 (range 2-6). The course was not determinable in 4 patients (10%). Nineteen women (49%) had 22 further deliveries after the first manifestation of the illness. The frequency of a relapse in connection with further pregnancy or delivery was 50%. Applying the Strauss-Carpenter Outcome Scale, we found a favourable outcome for the total sample with a mean value of 14.1 (SD = 2.6). The vast majority of patients (75%) showed no persistent alterations. Our findings provide further evidence of a favourable prognosis of severe postpartum psychiatric disorder despite the remarkably high rate of puerperal relapses.

[Agenesis septum pellucidum in a schizophrenic patient]. / Isolierte Aplasie des Septum pellucidum bei einem hebephrenen Patienten.

Absence of the septum pellucidum is a rare developmental disorder of the human brain. Previous reports focused on the association with other cerebral anomalies. We present MRI scans showing an isolated absence of the septum pellucidum. The patient was suffering from a schizophrenic psychosis. Mental retardation or epileptic seizures, which are often found in more complex developmental brain disorders, were not observed. The septal area is part of the limbic system and aplasia of the septum pellucidum could indicate developmental anomalies of the limbic system. The concept of cerebral maldevelopment and the limbic system in schizophrenic psychosis is discussed.